Hepatocyte growth factor (HGF) was isolated as a substance that enhanced hepatocyte growth, and its gene was cloned in 1989. In a model of experimental rats with 70% partial hepatectomies, HGF production in liver stromal cells and distant organs, such as lung and kidney, was reported to contribute to liver regeneration. Such liver regeneration is further enhanced in mice administered with recombinant HGF and HGF-expressing transgenic mice.
Clinical findings also show that hepatitis and hepatic disorders increase blood HGF level and that HGF activity decreases rapidly when liver regeneration is completed. HGF is thus thought to play an important role in liver regeneration. HGF is known to not only function as a regeneration factor in pathological conditions, such as drug-induced hepatitis, fulminant hepatitis, alcoholic hepatitis, and cirrhosis, but also to induce tissue regeneration in pulmonary fibrosis, nephrosclerosis, cardiac myopathy, and the like, thereby inhibiting the progression of fibrosis. Thus, HGF replacement therapy is expected to be a novel regeneration medical therapy that inhibits progression of intractable organ diseases and improves pathological conditions.
HGF is secreted as an inactive single-chain precursor. Intramolecular cleavage by HGF activator (HGFa), an activating enzyme specific to HGF, results in formation of the active two-chain HGF.
HGFa is one type of serine protease and is secreted in the form of single-chain pro-HGFa in the liver, and converted through limited proteolysis by thrombin into two-chain active HGFa.
Based on various findings, activated protein C (aPC) is thought to be effective in treating and preventing thrombosis, sepsis, and such (Non-patent Documents 1 to 3).
Protein C inhibitor (PCI) was discovered as a biological substance that inhibits the coagulation regulatory factor aPC (Non-patent Document 4). PCI irreversibly inhibits the enzymatic activity of aPC by forming an acyl enzyme complex with aPC (Non-patent Document 5). In addition, PCI also inhibits thrombin/thrombomodulin (Thr/TM) complex, which is an aPC-producing enzyme, to suppress production of aPC (Non-patent Document 6). In other words, PCI inhibits both production and activity of aPC, thereby suppressing the action of aPC. Therefore, the inhibition of PCI activity can enhance the activity of aPC produced endogenously and aPC administered exogenously, and thus can obtain an effective anti-blood coagulation action. The present inventors therefore prepared anti-PCI antibodies with the activity of neutralizing PCI, which inhibits the production and enzymatic activity of aPC (Patent Document 1). Such neutralizing antibodies suppress the blood coagulation system by enhancing the aPC activity, and are thus extremely useful for treating and preventing thrombosis. Further, when used in combination with aPC in the treatment of sepsis and such using aPC, these antibodies can be used as pharmaceutical agents that enhance aPC actions by suppressing aPC inactivation in blood.
In addition to the action described above, PCI was reported to have the action of inhibiting the HGFa activity by forming a complex with HGFa (Patent Document 2). However, whether or not PCI actually has the action of suppressing or retarding liver regeneration is unknown.    [Patent Document 1] International Patent Application Publication No. WO 04/065418 pamphlet    [Patent Document 2] Japanese Patent Application Kokai Publication No. (JP-A) 2002-273 (unexamined, published Japanese patent application)    [Non-patent Document 1] J. Biol. Chem. (2001) 276, 11199-203    [Non-patent Document 2] J. Clin. Invest. (1987) 79, 918-25    [Non-patent Document 3] Blood (1991) 78, 364-8    [Non-patent Document 4] J. Clin. Invest. (1980) 66, 1186-9    [Non-patent Document 5] J. Biochem. (1984) 95, 187-95    [Non-patent Document 6] Blood (1998) 91, 1542-7